Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models. J Med Chem 2016 Jan 28;59(2):578-91
Date
12/26/2015Pubmed ID
26704965Pubmed Central ID
PMC8317212DOI
10.1021/acs.jmedchem.5b01153Scopus ID
2-s2.0-84970916717 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
Author List
Cheng J, Giguere PM, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Huang XP, Zhu H, McCorvy JD, Wetsel WC, Roth BL, Kozikowski APAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain
Catalepsy
Central Nervous System Stimulants
Cognition
Dextroamphetamine
Drug Design
Drug Evaluation, Preclinical
Ether-A-Go-Go Potassium Channels
Female
Humans
Hyperkinesis
Male
Mice
Mice, Inbred C57BL
Microsomes, Liver
Prepulse Inhibition
Receptor, Serotonin, 5-HT2C
Schizophrenia
Schizophrenic Psychology
Serotonin 5-HT2 Receptor Agonists
Structure-Activity Relationship
Substrate Specificity
